The present invention relates generally to the field of cancer treatments, as well as to the field of peptide and non-peptide pharmaceutical compounds.
Many lung and prostate cancers, of which small cell lung cancer (SCLC) is a prime example, have a neuroendocrine phenotype, and their growth is stimulated by neuropeptides. Antagonists of several peptides (e.g. bradykinin, substance P, bombesin) have been used in experimental treatment of models of SCLC in animals. Among the most potent of the peptides examined thus far, crosslinked dimers of certain bradykinin antagonist peptides have been efficacious both in vitro and in vivo against strains of SCLC and other tumors Chan et al., Immunopharmacology 33: 201-204, 1996; Stewart et al., Can. J Physiol. Pharmacol 75: 719-724, 1997; Stewart et al., U.S. Pat. No. 5,849,863, issued Dec. 15, 1998). Prostate cancers show a similar neuroendocrine phenotype and are susceptible to neuropeptide antagonists.
The present invention provides anti-cancer agents (ACA) comprised of a range of novel amino acid derivatives and small peptides having the ability to inhibit growth of SCLC and certain other tumor cell lines (such as non-small cell lung cancer (NSCLC) and prostate cancer) in standard in vitro tests, as well as certain monomeric peptides that show inhibition of tumor growth in vivo. Certain of the peptides have a general structural relationship to carboxy-terminal fragments of bradykinin antagonists, but the non-peptides show no such general relationship. Monomers, dimers, trimers, tetramers, pentamers and cyclized analogs of the novel molecules are described. The new compounds are tested for bradykinin antagonist activity in standard assays, but there is no apparent relationship between bradykinin antagonist activity and cytolytic potency. All of the molecules described possess both hydrophobic (usually aromatic) and basic groups in their structures. Without being held to one particular theory, it appears that the compounds function by stimulation of cell death (apoptosis) in the tumor cells.
The present invention also provides compounds and methods for inhibiting cancer by administering to a subject afflicted with cancer (ie. of the lung or prostate) a therapeutically effective amount of one or more of the compounds herein described.
In general, the anti-cancer compounds are described by the formula:
[ACA]n-Xxe2x80x83xe2x80x83[Formula I]
wherein X is a linker having 2-5 functional groups or is absent, n=1-5, and ACA is selected from the group consisting of Formula II, Formula III, Formula IV, Formula V, and Formula VI. Other compounds described herein are defined by the Formula VII. The specifics regarding structure are enumerated in the Detailed Description, Examples and Claims. Certain physical charateristics are enumerated in the Examples as well as the Detailed Description, Examples and Claims.